Nephrol Dial Transplant (2002) 17: 53-57
© 2002 European Renal Association-European Dialysis and Transplant Association
In vivo time-course of receptor binding in the parathyroid gland of the vitamin D analogue [3H]1,25-dihydroxy-22-oxavitamin D3 compared with [3H]1,25-dihydroxyvitamin D3, determined by micro-autoradiography
1 Chugai Pharmaceutical Co., Ltd, Gotemba, Shizuoka, Japan and 2 International Institute of Drug Distribution Cytopharmacology and Cytotoxicology, Chapel Hill, North Carolina, USA
Abstract
1,25-Dihydroxy-22-oxavitamin D3 (22-oxacalcitriol, OCT), is a new synthetic analogue of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), to be used in the treatment of secondary hyperparathyroidism. This study used receptor micro-autoradiography in the parathyroid gland to determine and compare the time-course of receptor binding between OCT and 1,25(OH)2D3. Mice were injected with 4 µg/kg of [26-3H]OCT or [26,27-methyl-3H]1,25(OH)2D3, and killed at 5, 15, 30 min, 1, 2, 4, 8, 12, and 24 h afterwards. Thyroid-parathyroid tissue was excised and autoradiograms were prepared. Under identical conditions of dose and adjusted specific radioactivity between [3H]OCT and [3H]1,25(OH)2D3, the plasma concentration of [3H]OCT was much lower than that of [3H]1,25(OH)2D3. In the parathyroid at all time points, chief cell nuclei were labelled with varying degrees while connective tissue cells remained unlabelled. Nuclear receptor binding of [3H]OCT appeared equal to or higher than that of [3H]1,25(OH)2D3. Nuclear uptake of [3H]OCT was maximal at 15 min and higher than that of [3H]1,25(OH)2D3, which was maximal at 1 h after injection. Low levels of nuclear retention of the two compounds were still similarly detectable at 12 h. The results indicate the high affinity of OCT to parathyroid cells, and suggest that OCT has a higher therapeutic potential than 1,25(OH)2D3, especially under clinical conditions, at which OCT with its lower calcaemic effect would allow treatment with a dose several times higher than 1,25(OH)2D3.
Keywords: autoradiography; nuclear uptake; OCT; parathyroid gland; receptor binding; vitamin D analogue
Notes
Correspondence and offprint requests to: Nobuo Koike, PhD, Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. Email: koikenbo{at}chugai\|[hyphen]\|pharm.co.jp
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